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Neuroprotection by Cell Permeable TAT-mGluR1 Peptide in Ischemia: Synergy Between Carrier and Cargo Sequences

^* To whom correspondence should be addressed. E-mail: baudry{at}usc.edu.

	Abstract

Overactivation of glutamate receptors is a critical mechanism for neuronal death in ischemic stroke. Previously, we reported that overactivation of N-methyl-D-aspartate (NMDA)–type glutamate receptor induced calpainmediated truncation of metabotropic glutamate receptor mGluR1, resulting in suppression of its neuroprotective signaling pathway. A fusion peptide containing the transactivating regulatory protein (TAT) protein transduction domain (PTD) and the mGluR1 sequence spanning the calpain cleavage site effectively blocked mGluR1 truncation and protected neurons against NMDA-induced neuronal toxicity. We recently evaluated the role of this mechanism in ischemia-induced cell death. We found that mGluR1 was truncated in both in vitro and in vivo models of stroke and that this truncation was accompanied by the typical calpain-mediated proteolysis of spectrin. The TAT-mGluR1 fusion peptide produced robust neuroprotective effect in the in vitro model of stroke. In addition, we found that the TAT protein transduction domain peptide itself altered the function of membrane channels through some unknown mechanisms and showed some mild neuroprotective effects. Together, these experiments indicated a synergistic relationship between the TAT carrier sequence and the mGluR1 peptide cargo sequence, and this synergy might account for the neuroprotective properties of the TAT-mGluR1 peptide. DOI: 10.1177/1073858407309762

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